The present invention is generally related to heterocyclic compounds and more particularly to substituted heterocyclics useful as NDMA receptor selective subtype blockers for modulation neuronal activity and plasticity.
The present invention relates to compounds of the general formula 
wherein
Ar1 is pyridyl or phenyl, substituted by hydroxy, lower alkyl, halogen, amino, nitro. benzyloxy or lower alkoxy-lower alkoxy, or is the group 
xe2x80x83wherein
Z1 is a five membered heterocyclic ring, which contains one or two heteroatoms, selected from N or O;
R1 is hydrogen, hydroxy or an oxo group;
Ar2 is pyridyl or phenyl, optionally substituted by hydroxy, lower alkyl, halogen, amino, nitro, benzyloxy or lower alkoxy-lower alkoxy, or is the group 
xe2x80x83wherein
Z2 is a five or six membered ring, which optionally contains one or two heteroatoms, selected from N or O; and
Q is xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94;
X is a bond, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94(CH2)nxe2x80x94;
A is a bond or xe2x80x94(CHR)mxe2x80x94;
R is hydrogen, halogen or hydroxy, independently from each other if m is 2 or 3;
Y is xe2x80x94(CR2)mxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, piperidin-1-yl, pyrrolidin-1-yl or C4-C6-cycloalkyl, which rings are optionally substituted by hydroxy;
B is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94(CHR)m;
n is 1 or 2; and
m is 1, 2 or 3;
and to pharmaceutically acceptable acid addition salts thereof.
Excluded from the scope of formula I are those compounds, wherein A and B are simultaneously a bond and Y is xe2x80x94CHRxe2x80x94. These compounds have been described in EP 160 436, useful as antiarrhytmic agents.
The present invention embraces racemic mixtures and all their corresponding enantiomers.
The compounds of formula I and their salts are distinguished by valuable therapeutic properties. Compounds of the present invention are NMDA (N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
Under pathological conditions of acute and chronic forms of neurodegeneration over-activation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two sub-unit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two sub-unit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 sub-units result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, chronic and acute pain.
Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, the manufacture of such medicaments and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier, and, respectively, for the manufacture of corresponding medicaments.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. Preferred are groups from 1 to 4 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residue is as defined above.
A xe2x80x9cfive membered heterocyclic ring, which contains one or two heteroatoms, selected from N or Oxe2x80x9d denotes, for example, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolidinyl or pyrazolinyl.
A xe2x80x9cfive or six membered ring, which optionally contains one or two heteroatoms, selected from N or Oxe2x80x9d are, for example; cyclopentyl, cyclohexyl, oxazolyl, isoxazolyl, furyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidyl, piperazinyl or morpholinyl.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I in the scope of the present invention are those, wherein Ar1 is phenyl, substituted by hydroxy, Q is xe2x80x94Sxe2x80x94, Ar2 is phenyl and X is xe2x80x94CH2. These are the following compounds:
(S)-4-[1-(4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(RS)-4-[1-(4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(R)-4-[1-(4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2R,3S) or (2S,3S)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2S,3S) or (2S,3S)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(RS)-4-[1-(3-phenyl-propyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(3RS,3RS) and (3RS,3SR)-4-[1-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2S,3R) or (2R,3R)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol,
(2RS,3S)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol or
(2RS,3R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidin-3-yl-sulfanyl]-phenol.
Compounds of the present invention, in which Ar1 is phenyl, substituted by hydroxy, Q is xe2x80x94S(O)xe2x80x94, Ar2 is phenyl and X is xe2x80x94CH2xe2x80x94 are further preferred, for example the following compound:
(3RS,S-oxide RS) and (3RS,S-oxide SR)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol,
(2R,3R,S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol,
(2S,3S,S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol,
(2R,3S,S-oxide R)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol or
(3S,S-oxide S) or (3S,S-oxide R)-4-[1-(2,2-difluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol.
Further preferred are compounds, in which Ar1 is phenyl, substituted by hydroxy, Q is xe2x80x94S(O)2xe2x80x94, Ar2 is indanyl or phenyl, optionally substituted by methyl and X is xe2x80x94CH2xe2x80x94 or xe2x80x94CH(OH)xe2x80x94, for example the following compounds:
(S)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(RS)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(2R,3S) and (2S,3S)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,(3RS,cis) and (3RS,trans)-4-[1-(3-benzyl-cyclobutyl)-pyrrolidine-3-sulfonyl]-phenol,
(3RS,cis)-4-[1-(4-phenyl-cyclohexyl)-pyrrolidine-3-sulfonyl]-phenol,
(3RS,4RS)-4-(4-hydroxy-benzenesulfonyl)-1-(4-phenyl-butyl)-pyrrolidin-3-ol,
(RS)-4-[1-(4-m-tolyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(S)-4-[1-(3-phenyl-propyl)-pyrrolidine-3-sulfonyl]-phenol,
(R)-4-[1-(4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol,
(RS)-4-[1-(1-phenyl-piperidin-4-yl)-pyrrolidine-3-sulfonyl]-phenol or
(2R,3S) or (2S,3S)-4-[1-(2-hydroxy-4-phenyl-butyl)-pyrrolidine-3-sulfonyl]-phenol.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a secondary amine of formula 
xe2x80x83with an aldehyde or ketone of formula 
xe2x80x83to a compound of formula 
wherein Ar1, Ar2, Q, X, Y, R and B have the significance given above, or
b) oxydizing a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83and/or to a compound of formula 
wherein Ar1, Ar2, X, A, Y and B have the significance given above, or
c) reacting a secondary amine of formula 
xe2x80x83with a compound of formula 
xe2x80x83to give a compound of formula 
wherein L is a leaving group, such as Cl, Br or p-toluenesulfonate and Ar1, Ar2, Q, X, A, Y and B have the significance given above, or
d) reacting a secondary amine of formula 
xe2x80x83to with a compound of formula 
xe2x80x83to give a compound of formula 
wherein Ar1, Ar2, Q, X, Y and B have the significance given above, or
e) reacting a secondary amine of formula 
xe2x80x83with an aldehyde of formula 
xe2x80x83and with an alkyne of formula 
xe2x80x83to give a compound of formula 
wherein Ar1, Ar2, Q, X, R and B have the significance given above, or
f) reacting a compound of formula 
xe2x80x83with a compound of formula
Ar2hal
xe2x80x83to give a compound of formula 
wherein Ar1, Ar2, Q, X and A have the significance given above, or
g) cleaving off a O-protecting group of compounds of formula 
xe2x80x83to obtain a compound of formula 
wherein Ar1, Ar2, Q, X, A, Y and B have the significance given above and P is a O-protecting, group, for example benzyl or a methoxymethyl group, or
h) reducing a compound of formula 
xe2x80x83to a compound of formula 
wherein Ar1, Ar2, Q, X and B have the significance given above; or
i) reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83to obtain a compound of formula 
wherein Ar1, Ar2, Q, X, A and B have the significance given above; and
if desired, modifying one or more substituents within the definitions given above, or if desired, converting the compound of formula I obtained into a pharmaceutically acceptable salt.
In the following the preparation of compounds of formula I are described in more detail: 
wherein Ar1, Ar2, Q, Y, R and B have the significance given above.
Compounds of formula I (A is xe2x80x94CHRxe2x80x94) can be prepared by reacting a secondary amine of formula II with an aldehyde or ketone of formula III in the presence of a reducing agent like NaHB(OAc)3 in conventional manner. 
wherein Ar1, Ar2, X, A, Y, R and B have the significance given above. The compound of formula I-4 (Q is xe2x80x94SO2xe2x80x94) can be prepared by oxidation of compounds of formula I-3 (Q is xe2x80x94SOxe2x80x94), which itself can be prepared by oxidation of compounds of formula I-2 (Q is xe2x80x94Sxe2x80x94), using oxone(copyright) as oxidative agent. Oxone is a trade name for a stable oxidizing agent formed from a mixture consisting of 2KHSO5.KHSO4.KSO4. The oxidative agent and its use is described in Fieser and Fieser, Reagents for Organic Synthesis, vol. 1, (1967). 
Compounds of formula I can be prepared by reacting an amine of formula II with an electrophile compound of formula IV, wherein L is a leaving group like Cl, Br or p-toluenesulfonate and the remaining substituents are described above. 
wherein Ar1, Ar2, Q, X, Y and B have the significance given above.
Compounds of formula I-5, wherein A is xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94 can be prepared by reacting of an amine of formula II with an epoxide of formula V in conventional manner. 
wherein Ar1, Ar2, Q, X, R and B have the significance given above.
Compounds of formula I-6, wherein A is xe2x80x94CHRxe2x80x94 and Y is xe2x80x94Cxe2x89xa1Cxe2x80x94 can be prepared under Mannich conditions by reacting an amine of compound of formula II with an aldehyde of formula VI and an alkyne of formula VII. 
wherein Ar1, Ar2, Q, X and A have the significance given above.
Compounds of formula I-7, wherein Y is xe2x80x94CH2 and B is xe2x80x94CH2xe2x80x94 can be prepared under Suzuki conditions by reacting an alkene of formula VIII with Ar2hal, wherein hal is an, halogene like Br or I. 
wherein Ar1, Ar2, Q, X and A have the significance given above.
Alternatively, compounds of formula I-7, wherein Y is xe2x80x94CH2xe2x80x94 and xe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94 can be prepared in two steps under Heck conditions. Alkene compounds of formula VIII can react with Ar2hal, wherein hal is an halogen like Br or I to provide an alkene derivative of formula I-8 which can be subsequently hydrogenated to obtain compounds of formula I-7. 
wherein Ar1, Ar2, Q, X, A, Y and B have the significance given above and P is a O-protecting group, which may be, for example benzyl or methoxymethyl.
Compounds of formula I-9 or of compounds of formula I-10 can be prepared by cleaving off an O-protecting group of compounds of formulas X or XI. H2xe2x80x94Pd/C have been used to cleave a benzylether and acidic conditions have been used to cleave a methoxymethyl ether. 
wherein Ar1, Ar2, Q, X and B have the significance given above.
Compounds of formula I-11, wherein A is xe2x80x94CH2xe2x80x94 and Y is xe2x80x94CH2CH(OH)xe2x80x94 can be prepared by reducing a ketone of formula XII, which itself can be prepared by reacting an amine of formula II with a Michael acceptor of formula XIII. 
wherein Ar1, Ar2, Q, X, A and B have the significance given above.
Compounds of formula I-12 and I-13 can be prepared by reacting of an amine compound of formula XIV-1 or XIV-2 with boronic acid of formula XV. 
A compound of formula XIV-1 or of XIV-2 can be prepared by treating, the boc-protected amine compound of formula XVI-1 or XVI-2 with an acid, for example with trifluoroacetic acid. 
A compound of formula II can be prepared by hydrogenolysis of the benzylated amine of formula XVII, or by acidic hydrolysis of either the boc-protected amine compound of formula XVIII or the tosyl-protected amine compound of formula XIX. 
Compounds of formulas XVII, XVIII and XIX, wherein Q is xe2x80x94SO2xe2x80x94, can be prepared by oxidation of compounds, respectively XVII, XVIII and XIX, wherein Q is xe2x80x94SOxe2x80x94, which themselves can be prepared by oxidation of compounds, respectively XVII, XVIII and XIX, wherein Q is xe2x80x94Sxe2x80x94, using oxone or m-CPBA as oxidative agent.
Compounds of formulas XVII, XVIII and XIX , wherein Q is xe2x80x94Sxe2x80x94 can be prepared by reaction of a thiol of formula XXIII with respectively electrophiles of formulas XX, XXI and XXII, wherein Lxe2x80x2 is a leaving group, such as p-toluenesulfonate or mesylate. 
Alternatively, compounds of formula XVIII, wherein Q is xe2x80x94Sxe2x80x94 can be prepared by reacting, a thiol of formula XXIV with Ar1-hal in the presence of a catalytic amount of Pd2(dba)3 and DPPF.
Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium and
dppf is 1,1xe2x80x2-bis(diphenylphosphino)ferrocene. 
The monofluoro sulfoxides are obtained by oxidation of the corresponding sulfides with oxone. The sulfides are prepared by reduction of the amides with borane dimethylsulfide complex. The amides are accessible by coupling the racemic monofluoroacid with the R or S configured pyrrolidines in the presence of an activating agent like carbonyldimidazole. The racemic acid is prepared by saponification of the corresponding racemic methyl ester. This methyl ester as well as the R or S configured pyrrolidines have been described in more detail in the working examples. 
The difluoro sulfoxides are obtained by oxidation of the corresponding sulfides with oxone. The sulfides are prepared from the achiral difluoro alcohol after a Swern oxidation and reductive amination in the presence of an R or S configured pyrrolidine and sodium triacetoxyborohydride as reducing agent. The alcohol is obtained from the commercially available ethyl 2-oxo 4-phenylbutyrate after treatment with DAST ((diethylamino)sulfur trifluoride) and reduction with sodium borohydride.
The starting materials of formulas III, IV, V, VI, VII, XIII, XV, XX, XXI, XXII, XXIII, XXVI and XXIX are commercial products or can be prepared according to methods known per se.
Pharmaceutically acceptable salts can be manufactured according to methods which are known per se and familiar to any person skilled in the art. The acid addition salts of compounds of formula I are especially well suited for pharmaceutical use.
In schemes 1-10 and 15 and 16 are described processes for preparation of compounds of formula I, starting from known compounds, from commercial products or from compounds, which can be prepared in conventional manner. In schemes 11-14 are described processes for the preparation of intermediates.
The preparation of compounds of formula I are described in more detail in working examples 1-69.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable acid addition salts possess valuable pharmacodynamic properties. They are NMDA-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
The compounds were investigated in accordance with the test given hereinafter.
Male Fxc3xcllinsdorf albino rats weighing between 150-200 g were used. Membranes were prepared by homogenization of the whole brain minus cerebellum and medulla oblongata with a Polytron (10,000 rpm, 30 seconds), in 25 volumes of a cold Tris-HCl 50 mM, EDTA 10 mM, pH 7.1 buffer. The homogenate was centrifuged at 48,000 g for 10 minutes at 4xc2x0 C. The pellet was resuspended using the Polytron in the same volume of buffer and the homogenate was incubated at 37xc2x0 C. for 10 minutes. After centrifugation the pellet was homogenized in the same buffer and frozen at xe2x88x9280xc2x0 C. for at least 16 hours but not more than 10 days. For the binding assay the homogenate was thawed at 37xc2x0 C., centrifuged and the pellet was washed three times as above in a Tris-HCl 5 mM, pH 7.4 cold buffer. The final pellet was resuspended in the same buffer and used at a final concentration of 200 mg of protein/ml.
3H-Ro 25-6981 binding experiments were performed using a Tris-HCl 50 mM, pH 7.4 buffer. For displacement experiments 5 nM of 3H-Ro 25-6981 were used and non-specific binding was measured using 10 mM of tetrahydroisoquinoline and usually it accounts for 10% of the total. The incubation time was 2 hours at 4xc2x0 C. and the assay was stopped by filtration on Whatman GF/B glass fiber filters (Unifilter-96, Packard, Zxc3xcrich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the filter was counted on a Packard Top-count microplate scintillation counter after addition of 40 mL of microscint 40 (Canberra Packard S.A., Zxc3xcrich, Switzerland).
The effects of compounds were measured using a minimum of 8 concentrations and repeated at least once. The pooled normalized values were analyzed using a non-linear regression calculation program which provide IC50 with their relative upper and lower 95% confidence limits (RS1, BBN, USA).
The IC50 (xcexcM) of preferred compounds tested in accordance with the above mentioned methods are in the range of about 0.009-0.100.
Examples of some IC50 values of preferred compounds are given in the table below:
The compounds of formula I and their salts, as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application with the usual pharmaceutical adjuvant materials, for example, organic or inorganic inert carrier materials, such as, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in the range of about 0.1 mg per dosage to about 1000 mg per day of a compound of general formula I although the upper limit can also be exceeded when this is shown to be indicated.
The following examples illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner. All temperatures are given in degrees Celsius.